The present invention relates to methods of selecting agents for the treatment of hyperproliferative diseases such as cancer and to combinations of agents for the treatment of same.
The ErbB family of tyrosine kinase receptors and ligands which bind same play an important role in embryonic development, as well as in tissue remodeling throughout adulthood. The signaling cascade initiates with ligand binding, which leads to receptor dimerization and phosphorylation, and results in various cellular processes, including proliferation, differentiation, migration and survival.
There are four closely related ErbB receptors: ErbB-1 [epidermal growth factor receptor (EGFR)] which binds epidermal growth factor (EGF), transforming growth factor α (TGFα), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), betacellulin (BTC), epiregulin (EPR) and epigen; ErbB-3 and ErbB-4 which bind neuregulin growth factors; and ErbB-2 (HER2) which currently has no known ligands.
All ErbB family ligands share a 50-60 amino acid-long sequence containing six cysteines in a conserved spacing and context, collectively called the epidermal growth factor (EGF) motif. This motif is the central structural and functional feature responsible for receptor recognition. The growth factors are synthesized as type I transmembrane proteins and ectodomain shedding occurs (via proteolytic processing) which leads to the release of the soluble growth factor (comprising an EGF-like domain). The soluble ligand may in turn bind and activate receptors on distant cells, neighboring cells, or on the cells of its origin. Some membrane-anchored ligands can also activate EGFR on membranes of adjacent cells, a mechanism which may induce different biological outcomes than soluble ligands.
The ErbB proteins have been described in involvement of several pathologies, including psoriasis, arthrosclerosis, as well as in several types of human cancer. For instance, many tumors of epithelial origins express an increased level of ErbB-1 on their cell surface [Ullrich, A. et al. (1984) Nature 309, 418-425]. Tumors with increased ErbB receptor expression often display increased production of TGFα, or other ErbB ligands, allowing receptor activation by an autocrine loop.
Clinical studies indicate that overexpression of one or more ErbB ligands correlates with decreased patient survival. For example, widespread expression of TGFα within primary colorectal tumor specimens is associated with a greater than 50-fold increased risk of developing liver metastases [Barozzi, C. et al. (2002) Cancer 94, 647-657]. In bladder cancer, the elevated expression of a number of ErbB ligands (AR, HB-EGF, TGFα and particularly EPR) is linked to decreased patient survival [Thogersen, V. B. et al. (2001) Cancer Res 61, 6227-6233]. In addition, elevated TGFα expression in metastatic disease is associated with poorer patient outcome [De Jong, K. P. et al (1998) Hepatology 28, 971-979] and increased expression of TGFα in head and neck tumors is correlated with decreased patient survival [Grandis, J. R. et al. (1998) J Cell Biochem 69, 55-62]. Moreover, tumor cell expression of some ligands, notably TGFα, AR and HB-EGF, is associated with resistance to chemotherapeutics [Eckstein, N. et al. (2008) J Biol Chem 283, 739-750; Wang, F. et al. (2007) Oncogene 26, 2006-2016].
Emerging data indicates that the expression of specific ErbB ligands in certain tumors is differently associated with prognosis. EGF expression in breast tumor samples is associated with more favorable prognosis whereas TGFα expression is associated with a more aggressive tumor [Revillion, F. et al. (2008) Int J Biol Markers 23, 10-17]. Likewise, microarray analyses revealed that early hyperplastic precursors of breast cancer display increased AR transcription and decreased EGF transcription relative to normal breast tissues [Lee, S. et al. (2007) Am J Pathol 171, 252-262]. In patients with non-small cell lung carcinoma (NSCLC), TGFα and AR serum concentration correlate with tumor aggressiveness [Lemos-Gonzalez, Y. et al. (2007) Br J Cancer 96, 1569-1578]. Taken together, this data suggests that TGFα and AR are associated with EGFR-associated tumor cell aggressiveness and chemoresistance, while EGF may in fact antagonize stimulation of pathogenic signaling by TGFα and AR [Wilson, K. J. et al. (2009) Pharmacol Ther 122, 1-8].
Currently approved drugs for the treatment of ErbB associated cancers include monoclonal antibodies directed at ErbB-1 (EGFR, e.g. erbitux/cetuximab) or at HER2 (ErbB-2, e.g. herceptin/trastuzumab), or small-molecule tyrosine kinase inhibitors (TKI, e.g. tarceva/erlotinib) [Britten, C. D. (2004) Mol Cancer Ther 3, 1335-1342; Weiner, L. M., and Borghaei, H. (2006) Hum Antibodies 15, 103-111]. Acquired resistance to monoclonal antibodies (such as trastuzumab) or tyrosine kinase inhibitors (such as gefitinib) is often associated with up-regulation of ErbB receptors or ligands, for example, human breast cancer cells selected in vivo for resistance to trastuzumab remarkably overexpressed EGFR and the ErbB ligands TGFα, HB-EGF and NRG1 [Ritter, C. A. et al. (2007) Clin Cancer Res 13, 4909-4919]. Likewise, EGFR- and HER2-targeting monoclonal antibodies increase the anti-tumor effects of docetaxel by blocking functional receptors and drug evasion mechanisms [Bijman, M. N. et al. (2009) Anticancer Drugs 20, 450-460; Freeman, D. J. et al. (2009). Mol Cancer Ther 8, 1536-1546].
Additionally, alternative strategies that directly target ligands have been proposed. One such strategy is monoclonal antibodies specific for individual ligands. For example, bevacizmab is a humanized monoclonal antibody that binds vascular endothelial growth factor-A (VEGF-A) [Hurwitz, H., et al. (2004) N Engl J Med 350, 2335-2342; Shih, T., and Lindley, C. (2006) Clin Ther 28, 1779-1802]. Another strategy makes use of “ligand-traps”, soluble ligand-binding domains of specific receptors. An example for such a ligand-trap is etanercept, a fusion protein comprising the ligand-binding domain of the TNF-α receptor fused to the human immunoglobulin G (IgG) Fc region, which is used for the treatment of rheumatoid arthritis [Mohler, K. M., et al. (1993) J Immunol 151, 1548-1561]. Another alternative is the inhibition of the shedding agents, members of the disintegrin and metalloproteinase (ADAM) family, which are thought to mediate the shedding of EGFR ligands, an event critical for the production of functional EGFR ligands [Kataoka, H. (2009) J Dermatol Sci 56, 148-153; Kenny, P. A., and Bissell, M. J. (2007) J Clin Invest 117, 337-345; Merchant, N. B., et al. (2008) Clin Cancer Res 14, 1182-1191].
Additional monoclonal antibodies targeting ErbB ligands have been described in the art. For example, PCT Publication No. WO 2009/026705 describes monoclonal antibodies targeting TGFα for the treatment of osteoarthritis.
U.S. Pat. No. 7,501,122 describes treatment with anti-ErbB2 antibody combinations. Specifically, U.S. Pat. No. 7,501,122 teaches treating cancer (e.g. breast cancer, colon cancer) using humanized anti-ErbB2 antibodies. The antibodies described by the teachings of the invention may be administered together or separately to blocks ligand activation of an ErbB receptor in cancers which overexpress epidermal growth factor receptor (EGFR) or EGFR ligands (e.g. EGF, TGF-α or HB-EGF) and thereby inhibit the growth of cancer cells.
U.S. Pat. No. 7,485,302 describes methods for treating cancer using anti-ErbB2 antibodies and chemotherapeutic agents. Specifically, U.S. Pat. No. 7,485,302 teaches the use a chemotherapeutic agent along with anti-ErbB2 antibodies for the treatment of cancer (e.g. breast cancer, lung cancer) which overexpresses epidermal growth factor receptor (EGFR) or ligands thereof (e.g. TGFα).